权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Design and Synthesis of Collybolide Probes for Kappa-Opioid Receptor

Kappa-阿片受体的 Collybolide 探针的设计与合成

基本信息

批准号：
10650913
负责人：
Indrajeet Sharma
金额：
$ 20.27万
依托单位：
UNIVERSITY OF OKLAHOMA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10650913
关键词：
Active Sites Affinity Agonist Analgesics Antipruritics Anxiety Binding Biological Assay Chemicals Clinical Computer Models Crystallization Data Development Docking Evaluation Exhibits GTP-Binding Proteins Generations Goals Lactones Lead Ligands MAPK3 gene Mediating Mental Depression Metabolic Modeling Morphine Mus National Institute of Mental Health Natural Products Neurosciences Opioid Analgesics Opioid agonist Organic Synthesis Pain Pain management Pathway interactions Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Phosphorylation Physical Dependence Property Proteins Pruritus Psychotropic Drugs Public Health Research Research Personnel Sesquiterpenes Signaling Protein Solubility Structure-Activity Relationship Synthesis Chemistry Testing Ventilatory Depression abuse liability addiction analog aqueous base beta-arrestin design drug candidate fungus high throughput screening in vivo in vivo evaluation interdisciplinary approach kappa opioid receptors mu opioid receptors novel novel therapeutics programs psychologic public health relevance radioligand receptor recruit salvinorin A scaffold screening program side effect therapeutically effective

项目摘要

Design and Synthesis of Collybolide Probes for Kappa-Opioid Receptor Abstract: While the mu-opiate analgesics such as morphine are effective for severe pain, their use is limited due to unwanted side effects such as respiratory depression, physical dependence, psychological addiction, abuse liability and itching. Studies suggest that selective kappa-opioid receptor (KOR) agonists biased towards G- protein signaling could be novel therapeutics to treat pain with reduced side effects. Deciphering the structural requirements essential for KOR selectivity through novel chemical probes is the first step in developing selective- and biased-KOR ligands. In the quest for new KOR chemical probes, we identified collybolide, a non-nitrogenous sesquiterpene natural product extracted from the mushroom Collybia maculata as a highly selective KOR agonist having in vivo analgesic and antipruritic activity. Collybolide has a furyl-δ-lactone core similar to that of salvinorin A, however differs from the latter in exhibiting functional selectivity along with a 50- fold higher potency in blocking non-histamine-mediated itch. The long-term goal of this research program is to develop KOR based analgesics and anti-pruritic drugs with reduced side effects. The objective of this project is the development of novel collybolide probes for identifying selective- and biased-KOR ligands with desirable pharmacological profiles for use in vivo. Our hypothesis is that rational structural diversification of collybolide will provide novel probes to gain important structural information that could lead to the development of effective therapeutics for the treatment of pruritus and pain with reduced side effects. Guided by strong preliminary data, this hypothesis will be tested by pursuing the following specific aims: 1) Synthesis and evaluation of first- generation collybolide probes for identifying selective-and biased KOR ligands; 2) Design, synthesis and in vivo evaluation of optimized collybolide analogues with drug-like properties to identify potential analgesics and anti-pruritus agents with reduced side-effects. The proposed research will be performed by a highly qualified team of researchers having synergistic expertise in natural products isolation, organic synthesis, and medicinal chemistry as well as in pharmacology, neuroscience, computational docking, and protein crystallization. The studies in this application will comprehensively examine the structure–activity relationships of collybolide and are expected to yield a set of selective- and biased-?OR ligands with the potential of becoming lead drug candidates for itch and pain with reduced side effects. Further, high-throughput screening at the NIMH-PDSP against 50 CNS receptors could find new hits, which could be optimized further to explore new therapeutic opportunities.

kappa -阿片受体胶体内酯探针的设计与合成